Obesity is linked with structural and functional changes in the gut microbiome.

The abundance and diversity of specific bacteria seem to favor energy harvest and metabolic pathways leading to obesity.

Therefore, the field of gut microbiota has risen as an area of great importance that can be manipulated to obtain optimal health.

Probiotics-induced changes in gut microbiota profile may mitigate host metabolic dysregulations accompanying obesity.

Probiotics have been shown to change the composition of the gut microbiota, improve gut integrity, and restore the microbial shifts that characterize obesity.

In animal studies, probiotic supplementation has been shown to be effective in improving physical and biochemical parameters, metabolic and inflammatory markers, as well as inducing alterations in the gut microbial diversity of obese models, whereas the results in humans are sparse and inconsistent.

The effects of various probiotic strains on human health are very different, and consequently, their potential efficacy in improving obesity and associated metabolic dysfunctions may vary significantly.

Puffy Lux

Obese People Have Altered Microbiomes

Obesity is a complex metabolic disease associated with an excessive amount of body fat.

Although not just a cosmetic problem, obesity increases the risk of many illnesses and health problems, such as heart disease, diabetes, high blood pressure, and certain types of cancer.

Obesity has now become a worldwide pandemic affecting approximately 1 in 3 individuals [1].

Despite notable efforts in the past decade to control the incidence of obesity, progress has been negligent in understanding and explaining the etiology, as well as the various mechanisms mediating the development of obesity, which may help to identify viable therapeutic approaches for treatment.

Among the collection of factors and their complex interactions that play a role in obesity, new, accumulating evidence suggests that the gut microbiota is an important contributor.

The gut microbiota or intestinal microflora represents the sum of all bacteria that are present in the gastrointestinal (GI) tract starting from the mouth and increasing in its density along the small and large intestine [2].

An accumulating body of evidence has outlined several possible mechanisms by which the gut microbiota can contribute to, and/or influence obesity.

Although so much is still unknown and debatable, thus far there is a general consensus that the gut microbiota is involved in obesity through mechanisms, such as dietary carbohydrate fermentation, lipogenesis, excess energy storage, and several other pathways including a wide range of metabolites, hormones, and neurotransmitters, some of which are known to control food intake and regulate energy balance [345].

Moreover, there is convincing evidence demonstrating that the composition and diversity of the gut microbiota is altered in obese rodents and humans when compared to lean counterparts.

For example, gut microbiota composition is changed when obesity is present resulting in an enrichment or reduction in the proportions of specific bacterial groups.

In a similar way, gut microbiota gene richness is also affected in obesity with studies showing a 20–40% decrease in the diversity of bacteria [67].

These conclusions suggest that the restoration of the compositional profile and richness of the gut microbiota may result in rescuing the obese phenotype and associated metabolic defects.

One way of achieving this is through the use of prebiotics, probiotics, and synbiotics. 

Weight Loss

Gut Microbiota Structure and Function

The intestinal gut microbiota is a complex organ system that is vital for the health and prosperity of the host.

In the last years, the gut microbiome, that encompasses the genes of all microbial cells, has been intensely scrutinized through genetic and molecular techniques of identification, including 16S ribosomal RNA gene sequencing, to determine what type of microorganisms reside in the gut and how they function [8].

There are approximately 101 to 103 cfu/mL of bacteria in the proximal small intestine, 104 to 107 cfu/mL of bacteria in the distal small intestine, and 104 to 1011 cfu/mL of bacteria in the large intestine (O’Hara and Shanahan, 2006).

The gut microflora consists of three main phyla: 1) Bacteroidetes (Porphyromonas, Prevotella, Bacteroides), 2) Firmicutes (Ruminococcus, Clostridium, Lactobacillus and Eubacteria), and 3) Actinobacteria (Bifidobacteria) [9], with the majority of the intestinal microbiota being represented by Bifidobacterium and  Bacteroides [10]

These microbes have important protective, structural, and metabolic functions and effects.

For example, the commensal bacteria in the gut microbiome protect the host by displacing harmful bacteria, competing with pathogens for nutrients, and producing anti-microbial compounds.

Also, these bacteria provide the host with structural functions, such as developing the immune system, inducing immunoglobulin A (IgA), and reinforcing the epithelial mucosal barrier.

In addition, the commensal bacteria provide metabolic functions to benefit the host by synthesizing substances, such as vitamin K, folate, and biotin, as well as participating in the absorption of minerals, such as magnesium, calcium, and iron ions.

These bacteria also metabolize dietary substrates and ferment non-digestible dietary compounds resulting in the formation of short-chain fatty acids (SCFAs).

The Gut Microbiome and Obesity Connection 

The link between gut microbiota and obesity has been proposed by early pioneering studies showing that adult mice devoid of gut microbiota (i.e., germ-free) acquired a 60% increase in body fat content after they were recolonized with a healthy cecal microbiota [1112].

The initial mechanism speculated to be responsible for such an increase in body fat levels was attributed to the ability of microbiota to extract energy from food constituents and regulate the energy balance of the host.

Degradation of dietary polysaccharides and fiber by Bacteroides and Firmicutes in the gut results in the production of short-chain fatty acids (SCFAs), such as propionate, acetate, and butyrate.

Propionate is a major energy source for the host via de novo synthesis of lipids and glucose in the liver [13].

Acetate is used in peripheral tissues as a substrate for cholesterol synthesis, while butyrate represents a rich energy source for colonic epithelial cells [14].

In addition, microflora is involved in the control of energy balance, food intake, and satiety via gut peptide signaling, through hormonal effects in the blood, or by direct modulation of the nervous system.

The appropriate balance of these regulatory peptides may be disrupted if the microbiota composition is changed, as has been showcased in germ-free mice having increased levels of pro-obesity peptides like neuropeptide-Y and reduced levels of anti-obesity peptides [15].

The gut is also involved in nutrient sensing, with metabolic byproducts from bacteria activating enteroendocrine cells (EEC) through paracrine signaling from enterocytes (cells of the intestinal lining) [16].

In vitro and in vivo studies have demonstrated that short-chain fatty acids (SCFAs) may be used as main energy source, but they also serve as signaling molecules that can activate G-protein coupled receptors (GPRs), including GPR43 (also known as free fatty acid receptor 2) in adipose and intestinal tissues [17]

In adipose tissue, short-chain fatty acids (SCFAs) bind to GPR43, promoting adipogenesis and increasing energy expenditure [18].

In intestinal tissue, SCFAs bind to GPR43 leading to secretion of anorexigenic (appetite-suppressing) peptides, including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), resulting in improved glucose tolerance and increased energy utilization.

Also, increased production of selected SCFAs is associated with high levels of the hormones ghrelin and insulin [16].

In particular, butyrate is involved in energy regulation by stimulating L cells, a subpopulation of enteroendocrine cells (EEC), to secrete glucagon-like peptide-1 (GLP-1).

GLP-1, a peptide involved in satiety and insulin secretion, has been found to be lower in obese compared to lean individuals [19].

Similarly, peptide YY (PYY), also produced by the intestinal L cells, is important for satiety, and increases in concentration during the postprandial (after eating) period [20].

As such, the administration of PYY-3-36 in obese individuals results in significant reductions in food intake [21].

Consequently, GLP-1 and PYY act as appetite suppressants and are potent mediators of the gut-brain axis, which facilitate important cross-talk concerning energy homeostasis, digestion, and appetite [22].

These peptides decrease intestinal motility, delay gastric emptying, and regulate glucose homeostasis and energy utilization [23].

The orexigenic (appetite promoting) gastric peptide hormone, ghrelin, is negatively correlated with Bifidobacterium, Lactobacillus, and Blautia coccoides/Eubacterium rectale, and is positively correlated with Bacteroides and Prevotella.

Ghrelin has various functions including stimulation of gastric emptying, appetite stimulation, glucagon secretion, and inhibition of insulin secretion and thermogenesis.

It has been shown that cells that produce ghrelin have GPR43 receptors, but it is not clear yet if gut-derived metabolites directly stimulate these receptors, resulting in ghrelin secretion.

By contrast, the anorexigenic (appetite-suppressing) hormone leptin is positively correlated with Bifidobacterium and  Lactobacillus.

Even though it is not clear whether these are causal relationships, it is speculated that leptin can modulate gut microbiota by stimulating mucin production, which may favor differential bacterial growth [24].

Lastly, it should be mentioned that microflora composition can affect enteroendocrine cell (EEC) counts and their respective receptor expressions, as the Firmicutes to Bacteroidetes ratio was positively correlated with GPR43 expression in obese mice [25].

In summary, short-chain fatty acids (SCFAs) binding to GPR43 in both adipose and intestinal tissues regulate obesity and energy accumulation.

This mechanism helps in the maintenance of energy homeostasis and may be used as a tool in the treatment of metabolic diseases.

The gut microbiota not only increases lipogenesis, but also reduces levels of fast-induced adipose factor (FIAF), also called Angiopoietin-like 4 protein (ANGPTL4)- a lipoprotein lipase (LPL) inhibitor produced by the liver, intestine, and adipose tissue.

Fast-induced adipose factor (FIAF) is a main regulator of metabolism and adiposity [2627].

Increased intake of a high carbohydrate and fat diet can lead to dysbiosis and increased triglyceride deposition in adipose tissue, which is associated with decreased fast-induced adipose factor (FIAF) expression [12].

This, in turn, leads to enhanced adipocyte lipoprotein lipase (LPL) activity resulting in increased uptake of fatty acids, increased fat storage, and ultimately obesity [11].

As a result, fast-induced adipose factor (FIAF) serves as a protective mechanism against diet-induced obesity.

However, whether gut microbiota influences FIAF levels in obesity is still unclear, since high fat diet-induced obesity in germ-free mice only increases mRNA expression of FIAF in the intestine, but not in the circulation [28].

Furthermore, gut microbiota suppress the activity of AMP-activated protein kinase (AMPK), an important liver and skeletal muscle enzyme with a role in cellular energy homeostasis and obesity.

When energy expenditure is low, AMPK is decreased resulting in less activation of enzymes involved in beta-oxidation (fat burning), including acetyl CoA carboxylase and carnitine palmitoyltransferase I, thus leading to obesity [29].

This explains why germ-free mice fed a Western-type diet have increased levels of phosphorylated AMPK, which promotes fatty acid oxidation [29].

Thus, gut microbiota inhibits AMPK activity leading to heightened cholesterol and triglycerides synthesis, lipogenesis, excess fat accumulation, and obesity [30].

Obesity has also been linked to systemic, low-grade inflammation due to the failure of intestinal epithelial membrane receptor proteins that play a sensory role in the gut [313233].

Spring/Summer Banners

This causes increased gut permeability, reduced expression of tight junction proteins leading to bacterial fragments, such as lipopolysaccharides (LPS) to diffuse through the gut and into the bloodstream, resulting in metabolic endotoxemia.

LPS then combines with pattern recognition receptor CD14, which, together, are recognized by toll-like receptor-4 (TLR4), a major component of the innate immune system (non-specific defense) that maintains intestinal homeostasis.

Individuals who consume a high-fat diet have increased plasma LPS levels [3435], that stimulate cells through TLR4, leading to an increase in low-grade inflammation that is observed in obesity [3637].

Increased LPS plasma concentration, either via high-fat feeding or experimentally induced (i.e. through infusion), results in metabolic changes and systemic inflammation [38].

These changes are associated with a significant reduction in the population of Lactobacillus spp., Bifidobacterium spp., and Bacteroides–Prevotella spp in the gut.

On the contrary, administration of Bifidobacteria to rodents with thermal injury improved gut integrity and alleviated metabolic endotoxemia [39].

Another link between microbiota and obesity lies in the ability of Firmicutes and Actinobacteria  to produce conjugated linoleic acid (CLA).

Altered production of this fatty acid is worrying in the context of obesity, because CLA has been shown to exert several anti-obesity effects, including increased energy metabolism, energy expenditure, and lipolysis, as well as decreased adipogenesis and lipogenesis [40].

In addition, studies have shown that CLA decreases de novo lipid synthesis and induces adipocyte apoptosis (programmed cell death) [41].

Apoptosis of adipose tissue is associated with the induction of tumor Necrosis Factor-alpha (TNF-alpha) and uncoupling protein-2.

As the name implies, uncoupling protein-2 “uncouples” electron transfer across the inner mitochondrial membrane, which results in the thermal dissipation of energy, as opposed to its conversion to the energy storage molecule adenosine triphosphate (ATP) [42].

It is speculated that CLA mediates some of its effects by displacing arachidonic acid- a polyunsaturated omega-6 fatty acid – from the phospholipids contained in cell membranes, thereby decreasing synthesis of eicosanoids, like prostaglandins and leukotrienes, well-known players in inflammation.

Following irritation or injury, arachidonic acid is released and oxygenated by specific enzymes leading to the formation of eicosanoids, an important group of inflammatory mediators.

CLA possesses signaling functions as well, including the activation of transcription factors and peroxisome proliferator-activated receptors (PPARs), which have downstream effects on lipid metabolism and immune function [43].

Finally, when administered to mice, CLA enhanced sympathetic nervous system activity, which led to increased energy metabolism and reduced adipose tissue [44]

Bacterial Strains and Obesity

The ratio of the two prevalent bacterial phyla in the gut microbiota, Firmicutes and  Bacteroidetes that have been shown to produce short-chain fatty acids (SCFAs) from non-digested dietary substrates has been proposed as a marker for obesity.

For example, obese individuals tend to have a higher proportion of Firmicutes and a decreased proportion of Bacteroidetes [45].

Even though Bacteroidetes do possess the genes to produce enzymes involved in lipid and carbohydrate metabolism, Firmicutes possess significantly more resulting in increased fermented end products, including short-chain fatty acids (SCFAs) [4647]

Indeed, several studies have confirmed an increase in the ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, in obese individuals [48495051].

One study in particular has concluded that the prevalence of Bacteroides fragilis, a commensal gram-negative bacteria, is implicated in obesity [52].

However, the importance of the Firmicutes to Bacteroidetes  ratio remains controversial, as other studies have shown no correlation between the F/B ratio and obesity, and that no significant differences between the two phyla are present in obese individuals [5354].

Similarly, another recent study showed that Bacteroides vulgatus, one of the most abundant bacteria in the human gut and a pathobiont (a potentially pathological organism which under normal circumstances lives as a non-harming symbiont) was strongly associated with inflammation, insulin resistance, and altered metabolism.

Additionally, a reduction in several bacteria from the phylum Firmicutes, such as Blautia, Faecalibacterium, and others in the Clostridiales order, correlated with increased trunk-fat [55].

Also, several studies have shifted their attention to the relationship between non-bacterial, methanogenic archaea, and obesity.

Archaea are single-celled microorganisms with a cellular structure similar to bacteria. In particular, a reduction in Methanobrevibacter smithii has been linked with obesity [56].

M. smithii encourages fermentation and metabolism by using hydrogen, an end-product of fermentation.

A reduction in M. smithii may lead to decreased metabolism and an increased risk of obesity [45].

Other bacterial strains, such as Lactobacillus are also present in high quantities in obese and overweight children, whereas high levels of Bifidobacterium were found in lean children [52].

Lastly, a high prevalence of Faecalibacterium prausnitzii, the most abundant gram-positive commensal bacteria present in the gut, has also been linked with obesity [57].

Therefore, current research supports that microbiota compositional differences are present in obese compared to healthy, non-obese organisms.

The abundance or richness of bacterial genes has also been associated with obesity.

For example, low gene richness or counts (LGC) is correlated with increased trunk-fat and obesity.

In a large study involving 61 severely obese women, it was found that 75% of the subjects had low gene counts [55] compared to only 23–40% when subjects were overweight or moderately obese [67]

Furthermore, certain metabolites and the proteins involved in their metabolism were associated with low microbial gene richness (MGR).

For example, as trunk fat mass increases, microbial gene richness (MGR) decreases along with the metabolite, 3-methoxyphenylacetic acid.

This acid is a product of polyphenol and flavonoid fermentation and may have beneficial effects on the gut microflora.

As such, a reduction in histidine and enzymes involved in histidine production and degradation has also been implicated to be present in obesity.

Gamma-aminobutyric acid (GABA), a precursor neurotransmitter to histidine production that is linked to the downregulation of pro-inflammatory cytokines, is one such pathway that is negatively affected in obesity, leading to further inflammation [55].

Listing Management Tool

How Probiotics Affect the Gut Microbiota

Multiple studies have shown that the gut microbiota not only has a key role in the physiology of the host but also performs a modulatory role in obesity.

This implies that the manipulation of the gut microbiota through dietary or other means may confer beneficial effects by restoring gut functional integrity and reverse dysbiosis that is characteristic of obesity.

That type of approach is highly desirable, as it would decrease treatment costs and significantly diminish the risk of harm to the patient compared to more drastic and invasive interventions currently used to treat obesity, such as bariatric surgery.

In this respect, probiotics have been extensively studied and widely thought to be the intervention of choice in manipulating gut microbiota composition.

According to the World Health Organization (WHO) and the Food and Agricultural Organization, probiotics can be referred to as non-pathologic living microorganisms, that have been shown to confer health benefits to the host when administered in adequate amounts.

The term “probiotics” comes from the Greek word meaning “for life” [58].

Elie Metchnikoff was the first to observe the beneficial effects of fermented milk rich in lactic acid bacteria on the longevity of Bulgarian populations in the early 20th century.

Further developing Metchnikoff’s original research on the beneficial effects of bacteria, Henri Tissier at the Pasteur Institute in France, administered Bifidobacteria to infants suffering from diarrhea after discovering Bifidobacteria in the gut microbiota of human milk-fed babies [59].

Among the most well-studied probiotics are the lactic acid bacterial strains Bifidobacteria and  Lactobacilli, which have an established safety record and have been given GRAS (generally recognized as safe) status by the United States Food and Drug Administration.

Other bacterial probiotics that are still being explored include the genera Bacillus, Escherichia, and Propionibacterium [60].

Some general characteristics that serve in the identification of probiotic candidates include features that would facilitate colonization, such as tolerance to low pH, resistance to bile salts, and adhesion to host gut epithelium [61].

Probiotics interact with the host either in transit or by colonization with several downstream mechanisms underlying their health-promoting benefits.

Some of these mechanisms that are being currently studied include modification of the gut microbiota composition, strengthening of the gut epithelial barrier, competitive adherence to the gut mucosa, production of health-promoting and antimicrobial compounds, and modulation of the immune system to confer advantages to the host.

Conclusion

Obesity has wide-ranging and troublesome consequences not only in terms of health outcomes for individuals, but also in exerting a significant financial impact on society at large.

The clinical treatment of obesity has been met with significant challenges, mainly due to the complexity of its pathophysiology and the biopsychosocial variability among individuals.

Most formerly-approved medications for obesity have been removed from the market due to various adverse effects and the failure of obese individuals to maintain long-term weight loss.

While interventions, such as bariatric surgery can be effective in reducing excess weight for some individuals, the procedure is highly invasive, imposes great risk of unforeseen complications, and requires tremendous effort in adopting a new lifestyle.

These realities push the scientific and clinical community to develop innovative approaches to address this ever-growing problem, and among the potential solutions, probiotics, which are generally considered safe for human health, have shown some potential.

The human gut hosts trillions of bacteria, known collectively as the microbiota.

This diverse microbial ecosystem has evolved with us and is intricately linked to physiological processes that affect many organ systems, including cardiovascular, neural, immune, and metabolic.

Scientific research over the last few decades has shed light on the role of the microbiota in energy homeostasis regulation, and how dysbiosis may be implicated in the pathophysiology of obesity through particular hormonal, neural, or metabolic mechanisms.

Evidence thus far suggests that certain bacterial strains in specific proportions are associated with obesity, but which microbial community may be causally linked to obesity is still unknown.

PS. If you haven’t already, you may check out our Recommendations List for high-quality supplements, health products and services you can trust. There is probably nothing health-related you won’t find there + special discount codes are waiting for you.


You May Also Like


About George Kelly

George Kelly M.Sc is a Sports Nutritionist, Functional Nutritional Therapy Practitioner (FNTP), and Metabolic Type expert. He is the CEO and lead author of Metabolic Body.


References

[1] https://pubmed.ncbi.nlm.nih.gov/29177227/
[2] https://pubmed.ncbi.nlm.nih.gov/16819463/
[3] https://pubmed.ncbi.nlm.nih.gov/29533087/
[4] https://pubmed.ncbi.nlm.nih.gov/2773895/
[5] https://pubmed.ncbi.nlm.nih.gov/2000822/
[6] https://pubmed.ncbi.nlm.nih.gov/23985875/
[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412733/
[8] https://pubmed.ncbi.nlm.nih.gov/15831718/
[9] https://pubmed.ncbi.nlm.nih.gov/29854813/
[10] https://pubmed.ncbi.nlm.nih.gov/8324114/
[11] https://pubmed.ncbi.nlm.nih.gov/27105827/
[12] https://pubmed.ncbi.nlm.nih.gov/15505215/
[13] https://pubmed.ncbi.nlm.nih.gov/18180751/
[14] https://pubmed.ncbi.nlm.nih.gov/16782812/
[15] https://pubmed.ncbi.nlm.nih.gov/23892476/
[16] https://pubmed.ncbi.nlm.nih.gov/23724144/
[17] https://pubmed.ncbi.nlm.nih.gov/24926285/
[18] https://pubmed.ncbi.nlm.nih.gov/16123168/
[19] https://pubmed.ncbi.nlm.nih.gov/18931303/
[20] https://pubmed.ncbi.nlm.nih.gov/8059011/
[21] https://pubmed.ncbi.nlm.nih.gov/12954742/
[22] https://pubmed.ncbi.nlm.nih.gov/26542800/
[23] https://pubmed.ncbi.nlm.nih.gov/23295502/
[24] https://pubmed.ncbi.nlm.nih.gov/17495032/
[25] https://pubmed.ncbi.nlm.nih.gov/27892486/
[26] https://pubmed.ncbi.nlm.nih.gov/28421057/
[27] https://pubmed.ncbi.nlm.nih.gov/10866690/
[28] https://pubmed.ncbi.nlm.nih.gov/20441670/
[29] https://pubmed.ncbi.nlm.nih.gov/17210919/
[30] https://pubmed.ncbi.nlm.nih.gov/27098727/
[31] https://pubmed.ncbi.nlm.nih.gov/25228897/
[32] https://pubmed.ncbi.nlm.nih.gov/23478685/
[33] https://pubmed.ncbi.nlm.nih.gov/21633181/
[34] https://pubmed.ncbi.nlm.nih.gov/18469242/
[35] https://pubmed.ncbi.nlm.nih.gov/17991637/
[36] https://pubmed.ncbi.nlm.nih.gov/18305141/
[37] https://pubmed.ncbi.nlm.nih.gov/15260992/
[38] https://pubmed.ncbi.nlm.nih.gov/29934437/
[39] https://pubmed.ncbi.nlm.nih.gov/16967002/
[40] https://pubmed.ncbi.nlm.nih.gov/19954947/
[41] https://pubmed.ncbi.nlm.nih.gov/21775116/
[42] https://pubmed.ncbi.nlm.nih.gov/11334420/
[43] https://pubmed.ncbi.nlm.nih.gov/12055356/
[44] https://pubmed.ncbi.nlm.nih.gov/11485161/
[45] https://pubmed.ncbi.nlm.nih.gov/17183312/
[46] https://pubmed.ncbi.nlm.nih.gov/12480096/
[47] https://pubmed.ncbi.nlm.nih.gov/12361264/
[48] https://pubmed.ncbi.nlm.nih.gov/26261039/
[49] https://pubmed.ncbi.nlm.nih.gov/28532414/
[50] https://pubmed.ncbi.nlm.nih.gov/19043404/
[51] https://pubmed.ncbi.nlm.nih.gov/17183309/
[52] https://pubmed.ncbi.nlm.nih.gov/26551842/
[53] https://pubmed.ncbi.nlm.nih.gov/27228093/
[54] https://pubmed.ncbi.nlm.nih.gov/26230509/
[55] https://pubmed.ncbi.nlm.nih.gov/29899081/
[56] https://pubmed.ncbi.nlm.nih.gov/21829158/
[57] https://pubmed.ncbi.nlm.nih.gov/19849869/
[58] https://pubmed.ncbi.nlm.nih.gov/2666378/
[59] https://pubmed.ncbi.nlm.nih.gov/11157342/
[60] https://pubmed.ncbi.nlm.nih.gov/29090088/
[61] https://pubmed.ncbi.nlm.nih.gov/23488471/